Glioma is a highly challenging human malignancy as drugs typically exhibit a low blood-brain barrier (BBB) permeability as well as poor glioma selectivity and penetration. Here, we report that tandem nanomicelles cofunctionalized with brain tumor-targeting and cell-penetrating peptides, Angiopep-2 and TAT, enable a highly efficacious and specific anti-glioma chemotherapy. Interestingly, tandem nanomicelles with 20 mol% Angiopep-2 and 10 mol% TAT linked via long and short poly(ethylene glycol)s, respectively, while maintaining a high glioma cell selectivity display markedly enhanced BBB permeation, glioma accumulation and penetration, and glioma cell uptake. We further show that docetaxel-loaded tandem nanomicelles have a long blood circulation time in mice and significantly better inhibit orthotopic U87MG human glioma than the corresponding Angiopep-2 single peptide-functionalized control, leading to an improved survival rate with little adverse effects. These tandem nanomicelles uniquely combining brain tumor-targeting and cell-penetrating functions provide a novel and effective strategy for targeted glioma therapy. 

Y.Q. Zhu, Y. Jiang, F.H. Meng, C. Deng, R. Cheng, J. Zhang*, J. Feijen*, and Z.Y. Zhong*, Highly efficacious and specific anti-glioma chemotherapy by smart tandem nanomicelles co-functionalized with brain tumor-targeting and cell-penetrating peptides, J. Control. Release 2018, 278, 1-8.